These studies will provide new insights into the integration of innate immune activation pathways required for the recognition of microbiota at mucosal surfaces, a thematic goal shared between Project 1 and Project 4. In collaboration with Project 3, GEF-Hl was identified as an unexpected essential component of innate immune regulation. GEF-Hl functioned as part of Rip2 containing signaling complexes and was required for the induction of tyrosine phosphorylation of Rip2 essential for NF-KB activation. We will determine key mechanisms that allow GEF-H1 to mediated innate immune activation by regulating receptor-interacting protein (RIP) family kinases and non-receptor tyrosine kinases and examine the protein domains and posttranslational modifications of GEF-H1 responsible for the control of innate immune responses to microbial factors. New preliminary data obtained in work with Project 2, demonstrate that GEF-Hl further controls the activation of inflammatory pathways by the corticotropin receptors CRHR1 and CRHR2. In collaboration with Project 2, we will define the mechanisms by which GEF-H1 mediates neuropeptide dependent regulation of innate immune responses. In collaboration with Project 5 and supported by the isograft and xenograft model systems of Core B, we will determine whether inhibition of GEF-H1 effectors is a promising strategy for the promotion of mucosal recovery from intestinal inflammation.